Targeted Modulation of Intestinal Epithelial Regeneration and Immune Response in Ulcerative Colitis Using Dual-targeting Bilirubin Nanoparticles

Overview

Journal Theranostics

Date 2024 Jan 3

PMID 38169633

Authors

Zewei Zhuo

Kehang Guo

Yujun Luo

Qi Yang

Huihuan Wu

Ruijie Zeng

Rui Jiang

Jingwei Li

Rui Wei

Qizhou Lian

Weihong Sha

Yuliang Feng

Hao Chen

Affiliations

Soon will be listed here.

Abstract

The therapeutic benefits of bilirubin in the treatment of ulcerative colitis (UC) are considerable, whereas the underlying mechanism of bilirubin on UC remains unclear remains unexplored. In addition, the weak hydrophilicity and toxicity have limited its translational applications. We have developed a colon dual-targeting nanoparticle, for orally delivering bilirubin through hydrogel encapsulation of hyaluronic acid (HA)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles (HA-PLGA). Confocal microscopy and imaging were used to evaluate the uptake and the targeted property of HA-PLGA in UC. Immunohistochemistry, immunofluorescence, and transcriptomic analyses were applied to examine the therapeutic effect and potential mechanism of HA-PLGA in UC. Our results indicated that HA-PLGA can significantly enhance the release of bilirubin at simulated intestinal pH and demonstrate higher cellular uptake in inflammatory macrophages. Moreover, biodistribution studies revealed high uptake and retention of HA-PLGA in inflamed colon tissue of UC mouse model, resulting in effective recovery of intestinal morphology and barrier function. Importantly, HA-PLGA exerted potent therapeutic efficacy against ulcerative colitis through modulating the intestinal epithelial/stem cells regeneration, and the improvement of angiogenesis and inflammation. Furthermore, genome-wide RNA-seq analysis revealed transcriptional reprogramming of immune response genes in colon tissue upon HA-PLGA treatment in UC mouse model. Overall, our work provides an efficient colon targeted drug delivery system to potentiate the treatment of ulcerative colitis via modulating intestinal epithelium regeneration and immune response in ulcerative colitis.

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